This competitive renewal application seeks continued support for a long-standing and very productive project that uses rodent models to elucidate mechanisms underlying the behavioral effects of synthetic hallucinogenic drugs of abuse, including LSD and substituted amphetamines, and hallucinogenic natural products used in recreational, ritual, or religious contexts, including psilocybin mushrooms (psilocin), peyote cactus (mescaline), and Ayahuasca tea (DMT, 5MeODMT). Based on the profound effects of hallucinogens on responses to sensory and emotional stimuli in humans, hallucinogenic drug effects in rats and mice are assessed using two complementary behavioral paradigms that have direct counterparts in the study of human behavior. These translational paradigms are prepulse inhibition of the startle response, an operational measure of sensorimotor gating that is deficient in some psychiatric disorders, and rat and mouse Behavioral Pattern Monitors that provide a multivariate profile of exploratory and locomotor responses matching that used to assess psychiatric patients and psychostimulant abusers in the human Behavioral Pattern Monitor. These computerized systems assess activity, exploration, and behavioral organization - three major aspects of mammalian behavior in a novel environment. In addition, the hallucinogen-induced head-twitch response in rodents is used for specific questions. Selected drug studies are complemented by studies of mutant mice having specific deficits in serotonin or glutamate receptor subtypes. This combination of pharmacological and genetic manipulations provides converging approaches to hypothesis testing. The project has 3 specific aims. Aim 1 is to characterize and identify the mechanism by which synthetic equivalents of Ayahuasca tea ("Pharmahuasca") alter exploratory behavior in rats. Aim 2 tests specific hypotheses regarding the different serotonin receptor subtypes that mediate the behavioral effects of phenylalkylamine and indoleamine hallucinogens in mice. Given the important species differences in the effects of many serotonergic and dopaminergic drugs, these results will be compared with previous data from rats to better understand the relevance of the animal models to drug effects in humans. In light of the recent resumption of human studies with hallucinogens, and reports indicating that hallucinogens may possess clinical efficacy, a more complete understanding of the action of these drugs is urgently needed. Aim 3 is to test the hypothesis that metabotropic glutamatergic mGlu2/3 and mGlu5 receptors modulate the behavioral effects of serotonergic hallucinogens, extending recent findings suggesting that common pathways contribute to the effects of serotonergic and glutamatergic hallucinogens. These studies are responsive to PA-07-374 "Psychopharmacology of Widely Available Psychoactive Natural Products". This research uses behavioral measures that can be translated directly into parallel measures of human behavior to elucidate the neurobiological mechanisms responsible for the acute effects of hallucinogens, which presumably lead to the recreational use of these drugs of abuse. PUBLIC HEALTH RELEVANCE: Despite hundreds of years of human experimentation and recent increases in the use of hallucinogens either as religious sacraments or as "Club Drugs" in recreational contexts, very little is known about the brain mechanisms underlying the behavioral effects of hallucinogens. This long-standing project uses rodent models to identify the neurobiological mechanisms of action responsible for the effects of naturally occurring hallucinogens, such as psilocybin, mescaline, and Ayahuasca, and synthetic hallucinogens such as LSD. Such information is critical to understand the consequences of the use of these compounds and to provide models of psychosis that could help identify novel therapeutic targets for neuropsychiatric disorders.